Polymorphic forms of ivabradine hydrochloride

ABSTRACT

Stable crystalline Form II and stable crystalline Form III of ivabradine hydrochloride and processes for their preparation are disclosed.

FIELD OF THE INVENTION

The invention relates to novel polymorphic forms of ivabradinehydrochloride. More particularly, the invention relates to stablecrystalline Form II and stable crystalline Form III of ivabradinehydrochloride and processes for their preparation. Further, theinvention also relates to pharmaceutical compositions that include thestable crystalline Form II and the stable crystalline Form III ofivabradine hydrochloride.

BACKGROUND OF THE INVENTION

Ivabradine hydrochloride,3-{3-{{[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}(methyl)amino}-propyl}-7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-onehydrochloride of Formula (I) has very valuable pharmacological andtherapeutic properties, especially bradycardic properties, making ituseful in the treatment or prevention of various clinical situations ofmyocardial ischemia such as angina pectoris, myocardial infarct andassociated rhythm disturbances, and also of various pathologiesinvolving rhythm disturbances, especially supraventricular rhythmdisturbances, and in the treatment of heart failure.

The preparation and therapeutic use of ivabradine and salts thereof witha pharmaceutically acceptable acid, and especially its hydrochloride,have been described in the European Patent EP 0534859. The patentdescribes the synthesis of ivabradine hydrochloride by reacting thecompound of Formula (V-a) with the compound of Formula (IV-a):

to give a compound of Formula (II-a), the catalytic hydrogenation ofwhich results in ivabradine, which is then converted into itshydrochloride:

The disclosed process yielding ivabradine hydrochloride in only a verylow yield-less than 17% over the 3 steps as a whole.

Another process for preparing ivabradine is disclosed in U.S. Pat. No.5,296,482. According to the process, (+)-isomer of ivabradine is treatedwith aqueous HCl and then recrystallization in acetonitrile leads to theformation of ivabradine hydrochloride salt having m.p. 135-140° C.

International (PCT) Publication WO 2008/146308 A2 discloses process forthe preparation of ivabradine hydrochloride by treating ivabradine withalcoholic hydrogen chloride. The specification also discloses theamorphous form of ivabradine hydrochloride and process for itspreparation using suitable acid addition salts of ivabradine.

International (PCT) Publication WO 2008/065681 A2 discloses a processfor the preparation of ivabradine or the pharmaceutically acceptablesalts thereof which is incorporated herein as a reference in itsentirety.

International (PCT) Publication WO 2008/125006 A1 discloses a processfor the preparation of a crystalline form of ivabradine or thepharmaceutically acceptable salts thereof which is incorporated hereinas a reference in its entirety.

International (PCT) Publication WO 2011/098582 A2 discloses threecrystalline forms of ivabradine hydrochlorides like Form X, Form Z andForm K, which are incorporated herein as a reference in its entirety.

Polymorphism is the occurrence of different crystalline forms of asingle compound and it is a property of some compounds and complexes.Thus, polymorphs are distinct solids sharing the same molecular formula,yet each polymorph may have distinct physical properties. Therefore, asingle compound may give rise to a variety of polymorphic forms whereeach form has different and distinct physical properties, such asdifferent solubility profiles, different melting point temperaturesand/or different x-ray diffraction peaks. Since the solubility of eachpolymorph may vary, identifying the existence of pharmaceuticalpolymorphs is essential for providing pharmaceuticals with predicablesolubility profiles. It is desirable to investigate all solid-stateforms of a drug, including all polymorphic forms, and to determine thestability, dissolution and flow properties of each polymorphic form. Thepolymorphic forms of a compound can be distinguished in a laboratory byX-ray diffraction spectroscopy and by other methods such as, infraredspectrometry. For a general review of polymorphs and the pharmaceuticalapplications of polymorphs, See G. M. Wall, Pharm Manuf. 3, 33 (1986);J. K. Haleblian and W. McCrone, J. Pharm. Sci., 58, 911 (1969); and J.K. Haleblian, J. Pharm. Sci., 64, 1269 (1975), all of which areincorporated herein by reference.

Several crystalline forms of ivabradine hydrochloride and theirprocesses for preparation have been disclosed, for example in U.S. Pat.Nos. 7,176,197 B2, 7,384,932 B2, 7,361,652 B2, 7,361,651 B2, 7,361,650B2, 7,361,649 B2, and 7,358,240 B2.

The known crystalline forms of ivabradine hydrochloride arepseudopolymorphs, which are very susceptible in presence of water. Theyare either hydrates like hemihydrate, monohydrate or tetrahydrate oranhydrous compounds. Therefore, the present invention provides newcrystalline form of ivabradine hydrochloride, which is stable and usefulfor pharmaceutical compositions that include the crystalline ivabradinehydrochloride.

SUMMARY OF THE INVENTION

The inventors have discovered novel crystalline polymorphic forms ofivabradine hydrochloride and have developed processes for thepreparation of the crystalline forms. The new crystalline forms ofivabradine hydrochloride are designated as Form II and Form III.

In one general aspect there are provided novel crystalline Form II andcrystalline Form III of ivabradine hydrochloride.

The Form II of ivabradine hydrochloride may have the X-ray diffractionpattern of FIG. 1 and differential scanning calorimetry thermogram ofFIG. 2. The Form III of ivabradine hydrochloride may have the X-Raydiffraction pattern of FIG. 3.

In one general aspect there is provided a process for the preparation ofcrystalline Form II of ivabradine hydrochloride. The process includesproviding a solution of ivabradine hydrochloride in one or more organicsolvents to obtain ivabradine hydrochloride solution; and obtaining thecrystalline Form II of ivabradine hydrochloride by the removal ofsolvents.

In another general aspect there is provided a process for thepreparation of crystalline Form III of ivabradine hydrochloride. Theprocess includes contacting ivabradine hydrochloride with a preheatedone or more suitable solvent to obtain ivabradine hydrochloridesolution; and obtaining the crystalline Form III of ivabradinehydrochloride by the removal of solvents.

Removing the solvents may include, for example, one or more offiltration, filtration under vacuum, decantation, centrifugation,distillation, and distillation under vacuum.

Embodiments of the process may include one or more of the followingfeatures. For example, the solution of ivabradine hydrochloride may beprovided by heating ivabradine hydrochloride in one or more organicsolvents. The solution may be seeded with one or more crystals of FormII or Form III of ivabradine hydrochloride prior to the initiation ofproduct crystallization or the slurry may be cooled prior to filtration.

The process may include further drying of the product obtained. Theprocess may include further forming, of the product so obtained into afinished dosage form.

In another general aspect there is provided a pharmaceutical compositionthat includes a therapeutically effective amount of the crystalline FormII or crystalline Form III of ivabradine hydrochloride; and one or morepharmaceutically acceptable carriers, excipients or diluents.

In another general aspect there is provided a pharmaceutical compositioncomprising crystalline Form II of ivabradine hydrochloride substantiallyfree of one or more of its corresponding impurities as measured by HPLC.

In another general aspect there is provided a pharmaceutical compositioncomprising crystalline Form III of ivabradine hydrochloridesubstantially free of one or more of its corresponding impurities asmeasured by HPLC.

In another general aspect there is provided a stable crystalline Form IIof ivabradine hydrochloride which is substantially free from knowncrystalline forms β, δ, or γ or amorphous form.

In another general aspect there is provided a stable crystalline Form IIof ivabradine hydrochloride having water content from about 2.0% toabout 4.0% w/w.

In another general aspect there is provided a stable crystalline FormIII of ivabradine hydrochloride which is substantially free from knowncrystalline forms β, δ, or γ or amorphous form.

In another general aspect there is provided a crystalline ivabradinehydrochloride having particle size distributions wherein the 10^(th)volume percentile particle size (D10) is less than about 50 μm, the50^(th) volume percentile particle size (D50) is less than about 200 μm,or the 90^(th) volume percentile particle size (D90) is less than about400 μm, or any combination thereof, wherein the crystalline ivabradinehydrochloride may be crystalline Form-II or crystalline Form-III.

The details of one or more embodiments of the inventions are set forthin the description below. Other features, objects and advantages of theinventions will be apparent from the description.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an X-ray powder diffraction pattern of crystalline ivabradinehydrochloride Form II.

FIG. 2 is a Differential Scanning Calorimetry analysis of crystallineivabradine hydrochloride Form II.

FIG. 3 is an X-ray powder diffraction pattern of crystalline ivabradinehydrochloride Form III.

DETAILED DESCRIPTION OF THE INVENTION

The inventors have found new polymorphic forms of ivabradinehydrochloride and, in particular, the crystalline forms are designatedas Form II and Form III of ivabradine hydrochloride. The new forms arecharacterized by their respective X-ray powder diffraction pattern aswell as differential scanning calorimetry thermogram, as shown in FIGS.1, 2, and 3.

The inventors also have developed a process for the preparation of thecrystalline Form II of ivabradine hydrochloride, by providing solutionof ivabradine hydrochloride in one or more solvents to obtain ivabradinehydrochloride solution; and obtaining crystalline Form II of ivabradinehydrochloride by the removal of solvents.

The inventors have also developed a process for the preparation of thecrystalline Form III of ivabradine hydrochloride, by contactingivabradine hydrochloride with a preheated one or more suitable solventto obtain ivabradine hydrochloride solution; and obtaining thecrystalline Form III a ivabradine hydrochloride by the removal ofsolvents.

In general, the solution of ivabradine hydrochloride may be obtained bydissolving any known form of ivabradine hydrochloride in a suitablesolvent. The solution may be obtained by heating the ivabradinehydrochloride in a solvent. The resultant solution may be clarified toremove foreign particulate matter or treated with charcoal to removecoloring and other related impurities. The solution so obtained may beconcentrated to reduce the amount of solvent. The solution may beconcentrated by removing the solvent completely to get a residue.

Alternatively, such a solution may be obtained directly from a reactionin which ivabradine hydrochloride is formed. The solvent may be removedby a technique which includes, for example, filtration, filtration undervacuum, decantation, centrifugation, distillation and distillation undervacuum.

The inventors have found that the crystalline Form II of ivabradinehydrochloride is stable and is substantially free from known crystallineforms β, δ, γ, or amorphous form. The stable crystalline Form II ofivabradine hydrochloride has no detectable quantity of crystalline β, δ,γ, or amorphous forms after storage for 6 months at 40° C. and arelative humidity of 75% or at 25° C. and a relative humidity of 60%.

The inventors have found that the crystalline Form III of ivabradinehydrochloride is stable and is substantially free from known crystallineforms β, δ, γ, or amorphous form. The stable crystalline Form III ofivabradine hydrochloride has no detectable quantity of crystalline β, δ,γ, or amorphous forms after storage for 6 months at 40° C. and arelative humidity of 75% or at 25° C. and a relative humidity of 60%.

All ranges recited herein include the endpoints, including those thatrecite a range “between” two values. The terms such as “about”,“general”, “substantially” and the like are to be construed as modifyinga term or value such that it is not an absolute. Such terms will bedefined by the circumstances and the terms that they modify as thoseterms are understood by those skill in the art. This includes, at thevery least, a degree of expected experimental error, technique error andinstrument error for a given technique used to measure a value.

Thus, the advantage of the present invention is to provide storagestable crystalline forms of ivabradine hydrochloride which doesn'tchange to amorphous form and doesn't tend to decrease the water content.

When a molecule or other material is identified herein as “substantiallyfree”, it generally means, unless specified otherwise, that the materialis about 99% pure or more. In general, this refers to purity with regardto unwanted residual solvents, reaction byproducts, impurities andunreacted starting materials. In the case of substantially freecrystalline ivabradine hydrochloride, “free” also means about 99% of onecrystalline form free from known crystalline forms, as appropriate or inthe case of crystalline solids.

As used herein, stable crystalline Form II includes either: ivabradinehydrochloride that after exposure to a relative humidity of 75% at 40°C. or 60% at 25° C., for a period of at least six months does notcontain peaks at about 6.8°, 11.9°, and 15.9° 20 and having less thanabout 5% of known crystalline forms like β or δ or γ crystalline forms.In particular, it may contain less than about 1% crystalline forms likeβ or δ or γ crystalline forms, for example, it may not contain anydetectable amount of forms like β or δ or γ crystalline forms.

As used herein, stable crystalline Form III includes either: ivabradinehydrochloride that after exposure to a relative humidity of 75% at 40°C. or 60% at 25° C., for a period of at least six months does notcontains peaks at about 6.8° 20 and having less than about 5% of knowncrystalline forms like β or δ or γ crystalline forms. In particular, itmay contain less than about 1% crystalline forms like β or δ or γcrystalline forms, for example, it may not contain any detectable amountof forms like β or δ or γ crystalline forms.

As used herein, stable crystalline Form 11 includes either: ivabradinehydrochloride that after exposure to a relative humidity of 75% at 40°C. or 60% at 25° C., for a period of at least six months is having lessthan about 5% of amorphous form. In particular, it may contain less thanabout 1% amorphous form, for example, it may not contain any detectableamount of amorphous form.

As used herein, stable crystalline Form III includes either: ivabradinehydrochloride that after exposure to a relative humidity of 75% at 40°C. or 60% at 25° C., for a period of at least six months is having lessthan about 5% of amorphous form. In particular, it may contain less thanabout 1% amorphous form, for example, it may not contain any detectableamount of amorphous form.

As used herein, the term “obtaining” may include filtration, filtrationunder vacuum, centrifugation, and decantation to isolate product. Theproduct obtained may be further or additionally dried to achieve thedesired moisture values. For example, the product may be dried in a hotair oven, tray drier, dried under vacuum and/or in a Fluid Bed Drier.

“Suitable solvent” means a single or a combination of two or moresolvents. As used herein, the term “contacting” includes mixing, adding,slurrying, stirring, or a combination thereof.

In one general aspect, the invention provides a novel crystalline FormII of ivabradine hydrochloride characterized by X-ray powder diffractionpattern having characteristics peaks at about 15.50°, 18.02°, 19.00°,19.80°, 22.42°, 24.16°, and 25.46° (2θ).

The crystalline Form II of ivabradine hydrochloride is furthercharacterized by X-ray powder diffraction pattern having peakssubstantially as depicted in Figure-1. The crystalline Form II ofivabradine hydrochloride is further characterized by X-ray powderdiffraction pattern having characteristic peaks at degrees 2θsubstantially as depicted in Table-1 as herein below.

TABLE 1 Characteristic X-ray Powder Diffraction Pattern Peaks (expressedin 2θ ± 0.2° 2θ) and Relative Intensities of Diffraction Lines for FormII of Ivabradine Hydrochloride Degree 2θ ± 0.2° 2θ I/Io 8.05 6.6 8.694.7 9.00 2.0 9.83 3.2 11.17 2.0 12.11 6.2 12.73 1.3 14.68 1.4 15.50100.0 16.18 16.8 17.08 19.4 17.35 8.7 18.02 21.9 19.00 31.8 19.80 34.320.96 18.6 21.72 20.5 22.42 32.4 23.07 3.2 23.78 8.3 24.16 40.8 24.4626.8 25.14 11.1 25.46 21.6 26.16 3.0 26.60 7.1 27.36 12.7 27.85 9.328.57 4.1 29.83 2.9 30.82 5.5 31.32 6.8 31.70 5.2 32.76 4.1 33.72 4.834.58 2.0 34.95 1.9 35.61 3.0 37.25 2.2 37.81 3.1

The crystalline Form II of ivabradine hydrochloride is furthercharacterized by differential scanning calorimetry substantially asdepicted in Figure-2. It is further characterized by having one or moreof endothermic peaks in the range of 73° C.-78° C., in the range of 152°C.-159° C., and in the range of 197° C.-199° C.

In another general aspect, the invention provides a novel crystallineForm III of ivabradine hydrochloride characterized by X-ray powderdiffraction pattern having characteristics peaks at about 15.48°,16.18°, 19.00°, 19.78°, 24.12°, 24.41° (2θ).

The crystalline Form III of ivabradine hydrochloride is furthercharacterized by X-ray powder diffraction pattern having peakssubstantially as depicted in Figure-3.

The crystalline Form III of ivabradine hydrochloride is furthercharacterized by X-ray powder diffraction pattern having characteristicpeaks at degrees 2θ substantially as depicted in Table-2 as hereinbelow.

TABLE 2 Characteristic X-ray Powder Diffraction Pattern Peaks (expressedin 2θ ± 0.2° 2θ) and Relative Intensities of Diffraction Lines for FormIII of Ivabradine Hydrochloride Degree 2θ ± 0.2° 2θ I/Io 4.08 2.6 8.029.6 8.70 5.1 9.79 2.8 10.49 1.0 11.16 2.5 12.12 7.7 12.34 5.2 12.72 1.313.20 11.2 14.33 2.9 14.69 1.1 15.48 100.0 16.18 26.9 16.84 8.7 17.0313.6 17.33 5.8 17.98 21.7 19.00 25.7 19.78 33.1 20.92 24.9 21.70 15.722.38 24.4 24.12 39.8 24.41 26.2 25.44 16.9 26.14 7.0 26.56 4.8 27.3810.2 27.81 13.0 28.56 3.3 29.29 2.2 29.82 4.0 30.79 5.6 31.36 8.4 31.686.9 32.82 4.5 33.73 5.4 34.60 2.2 34.89 2.0 35.58 2.3 37.19 2.2 37.833.3 38.49 1.5

In another aspect, the present invention provides a process for thepreparation of crystalline Form II of ivabradine hydrochloride. Theprocess comprising: (a) providing solution of ivabradine hydrochloridein one or more suitable solvents to obtain ivabradine hydrochloridesolution; and (b) obtaining the crystalline Form II of ivabradinehydrochloride by the removal of the solvents.

In general, the suitable solvent as in step (a) comprises one or more ofmethanol, ethanol, isopropanol, butanol, dimethylformamide,dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, methyl ethylketone, acetone, methyl isobutyl ketone, ethyl acetate, butyl acetate,isopropyl acetate, acetonitrile, tetrahydrofuran,2-methyltetrahydrofuran, 1,4-dioxane, water, or mixtures thereof. Theremoving of solvent as in step (b) comprises one or more of filtration,filtration under vacuum, decantation, centrifugation, distillation anddistillation under vacuum.

The solution of ivabradine hydrochloride is provided in a mixture ofmethyl ethyl ketone and tetrahydrofuran from about ambient temperatureto about reflux temperature of mixture. In particular, the solution maybe heated at about 30° C. to about 120° C., more particularly from about35° C. to about 80° C. followed by cooling. The cooled solution issubjected to removal of solvents by the know techniques as disclosedherein above.

In another general aspect, the present invention provides a process forthe preparation of crystalline Form III of ivabradine hydrochloride. Theprocess comprising: (a) contacting ivabradine hydrochloride with apreheated one or more suitable solvent to obtain ivabradinehydrochloride solution; and (b) obtaining the crystalline Form III ofivabradine hydrochloride by the removal of the solvents.

In general, the suitable solvent as in step (a) comprises one or more ofdimethylformamide, dimethylacetamide, dimethylsulfoxide,N-methylpyrrolidone, acetone, methyl ethyl ketone, methyl isobutylketone, acetonitrile, water, or mixtures thereof. The removing ofsolvent as in step (b) comprises one or more of filtration, filtrationunder vacuum, decantation, centrifugation, distillation and distillationunder vacuum.

Embodiments of the process may include one or more of the followingfeatures. For example, the solution of ivabradine hydrochloride may beobtained by heating ivabradine hydrochloride in one or more organicsolvents. The solution may be seeded with one or more crystals of FormII of ivabradine hydrochloride prior to the initiation of productcrystallization or the slurry may be cooled prior to filtration.

According to further embodiments, the process further comprisingadditional drying of the ivabradine hydrochloride obtained. The dryingis carried out under for example in a hot air oven, tray drier, driedunder vacuum and/or in a Fluid Bed Drier. In general, the dryingcomprises at a temperature of above about 40° C. in hot air oven forabout 1 hour to about 12 hours. The drying may be done at about 40° C.to about 70° C. The process may include further forming of the productso obtained into a finished dosage form.

In another aspect, the present invention provides a process for thepreparation of crystalline Form II of ivabradine hydrochloride, theprocess comprising:

-   (a) contacting ivabradine base with hydrogen chloride in one or more    first solvents to obtain ivabradine hydrochloride;-   (b) obtaining the solution of ivabradine hydrochloride in one or    more second solvents to obtain ivabradine hydrochloride solution;    and-   (c) obtaining the crystalline Form II of ivabradine hydrochloride by    the removal of second solvents.

In general, the process includes contacting ivabradine base withhydrogen chloride in one or more first solvents. The first solventcomprises one or more of methanol, ethanol, isopropanol, butanol,dimethylformamide, dimethylacetamide, dimethylsulfoxide,N-methylpyrrolidone, methyl ethyl ketone, acetone, methyl isobutylketone, ethyl acetate, butyl acetate, isopropyl acetate, acetonitrile,tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, water, ormixtures thereof.

In general, the second solvent comprises one or more ofdimethylformamide, dimethylacetamide, dimethylsulfoxide,N-methylpyrrolidone, acetonitrile, tetrahydrofuran,2-methyltetrahydrofuran, 1,4-dioxane, water, or mixtures thereof.

According to another aspect, the present invention provides storagestable crystalline Form 11 and Form III of ivabradine hydrochloride.

In general, the storage stable crystalline Form II of ivabradinehydrochloride is substantially free from known crystalline forms β, δ,or γ. Further, the storage stable crystalline Form II of ivabradinehydrochloride is substantially free from amorphous form.

In general, the storage stable crystalline Form II of ivabradinehydrochloride is substantially free from known crystalline forms β, δ,or γ. Further, the storage stable crystalline Form II of ivabradinehydrochloride is substantially free from amorphous form.

According to another aspect, the present invention provides stablecrystalline Form II of ivabradine hydrochloride, wherein the Form II ofivabradine hydrochloride is having water content from about 2.0% toabout 4.0% w/w.

In another aspect, the present invention provides a process forpackaging crystalline ivabradine hydrochloride, the process comprising:

-   (a) placing crystalline ivabradine hydrochloride under nitrogen    atmosphere in a non-permeable bag and tying with a thread;-   (b) placing the bag of step (a) inside a black color polyethylene    bag, optionally containing oxygen busters and sealing it;-   (c) placing the bag of step (b) inside a triple laminated bag,    optionally containing oxygen busters and sealing it; and-   (d) placing the sealed triple laminated bag inside a high density    polyethylene (HDPE) container and sealing it.    wherein crystalline ivabradine hydrochloride comprises of Form II or    Form III.

In another general aspect, the storage stable crystalline Form-II ofivabradine hydrochloride may be characterized by at least 6 monthsstability results as outline in Table-III which is representative forone of the batch.

TABLE III 1 2 3 6 Month Months Months Month

40° C. ± 2° C./ 40° C. ± 2° C./ 40° C. ± 2° C./ 40° C. ± 2°

/ Sr. Initial 75% ± 5% 75% ± 5% 75% ± 5% 75% ± 5

No. Tests Specifications — RH RH RH RH 1. Description White to slightlyWhite White White White White yellow powder Powder Powder Powder PowderPowder 2. Water by KF (% Not more than 4.0% 2.1  2.0  2.0  2.1  2.0 w/w) 3. Impurity Profile (i) Tetrahydro Not more than 0.15 BDL BDL BDLBDL BDL benzazepine (ii) (S)-methyl Not more than 0.15 BDL BDL BDL BDLBDL amino Compd. (iii) Benzocylco Not more than 0.15 BDL BDL BDL BDL BDLbutane Compd. (iv) Dimer Impurity Not more than 0.15 BDL BDL BDL BDL BDL(v) Single Ind. Not more than 0.15 0.04 0.02 0.02 0.03 0.03 (vi) TotalImp. Not more than 0.15 0.09 0.05 0.03 0.08 0.09 4. Polymorph Form-IIForm-II Form-II Form-II Form-II Form-II BDL = Below Detection Limit

indicates data missing or illegible when filed

In another general aspect, the present invention accordingly provides apharmaceutical composition comprising a therapeutically effective amountof crystalline Form II of ivabradine hydrochloride and one or morepharmaceutically acceptable carriers, excipients or diluents.

In another general aspect, the storage stable crystalline Form III ofivabradine hydrochloride may be characterized by at least 6 monthsstability results as outline in Table-IV which is representative for oneof the batch.

TABLE IV 1 2 3 6 Month Months Months Months 40° C. ± 2° C./ 40° C. ± 2°C./ 40° C. ± 2° C./ 40° C. ± 2° C./ Sr. Initial 75% ± 5% 75% ± 5% 75% ±5% 75% ± 5% No. Tests Specifications — RH RH RH RH 1. Description Whiteto slightly White White White White White yellow powder Powder PowderPowder Powder Powder 2. Impurity Profile (i) Tetrahydro Not more than0.15 BDL BDL BDL BDL BDL benzazepine (ii) (S)-methyl Not more than 0.15BDL BDL BDL BDL BDL amino Compd. (iii) Benzocylco Not more than 0.15 BDLBDL BDL BDL BDL butane Compd. (iv) Dimer Impurity Not more than 0.15 BDLBDL BDL BDL BDL (v) Single Ind. Not more than 0.15 0.04 0.04 0.03 0.040.03 (vi) Total Imp. Not more than 0.15 0.09 0.07 0.06 0.08 0.09 4.Polymorph Form-III Form-III Form-III Form-III Form-III Form-III BDL =Below Detection Limit

In another general aspect, the present invention accordingly provides apharmaceutical composition comprising a therapeutically effective amountof crystalline Form III of ivabradine hydrochloride and one or morepharmaceutically acceptable carriers, excipients or diluents.

In further aspect, the present invention provides a pharmaceuticalcomposition comprising a therapeutically effective amount of a storagestable crystalline Form II of ivabradine hydrochloride having nodetectable quantity of crystalline β, δ, γ, or amorphous forms, and oneor more pharmaceutically acceptable carriers, excipients, or diluents.

In further aspect, the present invention provides a pharmaceuticalcomposition comprising a therapeutically effective amount of a storagestable crystalline Form III of ivabradine hydrochloride having nodetectable quantity of crystalline β, δ, γ, or amorphous forms, and oneor more pharmaceutically acceptable carriers, excipients, or diluents.

An aspect of the present application provides a pharmaceuticalcompositions comprising therapeutically effective amount of acrystalline Form II or Form III of ivabradine hydrochloridesubstantially free of one or more its corresponding impurities asmeasured by HPLC.

The impurities for ivabradine hydrochloride can be one or more of thefollowing.

-   S-methyl amine:    (S)-1-(4,5-dimethoxy-1,2-dihydrocyclobutanbenzen-1-yl)-N-methylmethamine.-   Tetrahydrobenzazepine: 7,8-Di    methoxy-1,3,4,5-tetrahydro-2H-3-benzazepine-2-one. BCP condense: (1    S)-4,5-Dimethoxy-1-(methylaminomethyl)benzocyclobutane    hydrochloride.-   Dimer impurity:    1-(4,5-Dimethoxy-1,2-dihydrocyclobutanebenzen-1-yl)-N-((4,5-dimethoxy-1,2-dihydrocyclobutanbenzen-1-yl)methyl-N-methylmethamine.

According to one aspect there is provided a pharmaceutical compositioncomprising a therapeutically effective amount of crystalline forms Form11 or Form III of ivabradine hydrochloride substantially free fromresidual methyl ethyl ketone.

An aspect of the invention provides crystalline Form II of ivabradinehydrochloride having particle size distributions, wherein the 10thvolume percentile particle size (D10) is less than about 50 μm, the 50thvolume percentile particle size (D50) is less than about 200 μm, or the90th volume percentile particle size (D90) is less than about 400 μm, orany combination thereof.

An aspect of the invention provides crystalline Form III of ivabradinehydrochloride having particle size distributions wherein the 10th volumepercentile particle size (D10) is less than about 50 μm, the 50th volumepercentile particle size (D50) is less than about 200 μm, or the 90thvolume percentile particle size (D90) is less than about 400 μm, or anycombination thereof.

In another aspect, the invention provides a process for the preparationof ivabradine hydrochloride which may be used starting material.

In general, the process for preparation of ivabradine hydrochlorideincludes a mixing ivabradine hydrochloride with one or more of suitablesolvent comprises tetrahydrofuran (THF), dimethylsulfoxide (DMSO),dimethylformamide, diethylether, dimethylether, water or a mixturethereof.

Embodiments of the process includes providing mixture of ivabradinehydrochloride, tetrahydrofuran (THF) and water under heating conditionsuntil dissolution is complete and the solution may be further cooleduntil crystallization is complete, and the product may be collected byfiltration. The product thus obtain may be dried to obtain of ivabradinehydrochloride or used as such for the further process steps to obtaincrystalline Form II or Form III.

The novel crystalline forms of ivabradine hydrochloride can becharacterized by any of the analytical technique like PXRD, DSC, IR asfollows:

(a) Characterization by PXRD

The X-ray powder diffraction spectrum was measured under the followingexperimental conditions:

Instrument X-Ray Diffractometer, D/Max-2200/ PC Make: Rigaku, Japan.X-Ray Cu/40 kv/40 mA Diverging 1° Scattering Slit 1° Receiving Slit 0.15mm Monochromator RS  0.8 mm Counter Scintillation Counter Scan ModeContinuous Scan Speed 3.000°/Min Sampling Width 0.020 Scan Axes TwoTheta/Theta Scan Range 2.000° to 40.000° Theta Offset 0.000°

(b) Characterization by Differential Scanning Calorimetry (DSC)

Analytical method: Differential scanning calorimetric analysis wasperformed using a Perkin Elmer Diamond DSC control unit and a DSC 300°C. differential scanning calorimeter. 2-5 mg samples were placed incrimped aluminum pans and heated from 50° C. to 300° C. in a liquidnitrogen atmosphere at a heating rate of 10° C./minute. Zinc-Indium wasused as the standard substance.

The present invention is further illustrated by the following exampleswhich are provided merely to be exemplary of the invention and do notlimit the scope of the invention. Certain modification and equivalentswill be apparent to those skilled in the art and are intended to beincluded within the scope of the present invention.

Example 1 Preparation of Ivabradine Hydrochloride (I)

100 g of ivabradine base and 300 mL acetonitrile were cooled to 0° C. to5° C. and acetonitrile hydrochloric acid solution was added drop wise byadjusting the pH to about 1-2. The resulting mass was stirred tillcomplete precipitation and maintained for 60 minutes. The product wasfiltered under nitrogen and washed with chilled acetonitrile. Thewet-cake and acetonitrile were heated at 60-65° C. and stirred for 30min. The reaction mixture was gradually cooled to 25° C. and stirred for1 hour. The product was filtered under vacuum and nitrogen atmosphere.The wet-cake was washed with chilled acetonitrile. The product was driedunder vacuum at 50-55° C. to obtain 75% 80 g crude ivabradinehydrochloride. The product was packed in double polyethene bag undernitrogen.

Example 2 Preparation of Ivabradine Hydrochloride (I)

100 g of ivabradine hydrochloride crude and 450 mL of THF were heated at60-65° C. 50 mL of water was added drop wise to get a clear solution at60-65° C. The reaction mixture was stirred for 30 minutes at the sametemperature and cooled slowly to 20-25° C. The reaction mixture wasstirred for 1.5 hour and filtered. The wet-cake was washed with THF andsuck dried under nitrogen for 30 min. The wet-cake and 450 mL THF wereheated again to get a clear solution at 60-65° C. and stirred for 30min. The reaction mixture was cooled at 25° C. and stirred for 1.5 hour.The product thus obtained was filtered to obtain 110 g wet-cake, whichwas used as such for the preparation of Form-II or Form-III.

Example 3 Preparation of Crystalline Form II of Ivabradine Hydrochloride(I)

20 g of ivabradine hydrochloride wet-cake and 200 mL of methyl ethylketone and tetrahydrofuran (10 mL) were heated at 75-80° C. for 15minutes to get a clear solution. The reaction mixture was stirred forfurther 60 minutes and cooled to 25° C. gradually. The reaction mixturewas stirred for 2 hours and filtered. The wet-cake was washed withmethylethyl ketone and dried under vacuum at 40° C. to 45° C. for 12hours. The X-ray powder diffraction discloses Form-II. (FIG. 1) and DSC(FIG. 2).

Example 4 Preparation of Crystalline Form II of Ivabradine Hydrochloride(I)

25 g of ivabradine hydrochloride wet-cake and 250 mL of methyl ethylketone and 12.5 mL tetrahydrofuran were heated at 40° C. for 15 minutesto obtain solution. The reaction mixture was stirred for further 60minutes and cooled to 25° C. gradually. The reaction mixture was stirredfor 2 hours and filtered. The wet-cake was washed with methylethylketone and dried under vacuum at 40° C. to 45° C. for 12 hours. TheX-ray powder diffraction discloses Form-II. (FIG. 1) and DSC (FIG. 2).

Example 5 Preparation of Crystalline Form III of IvabradineHydrochloride (I)

200 mL of methyl ethyl ketone was charged in a round bottom flask andthe temperature was raised to 50-60° C. 20.0 g of ivabradinehydrochloride was added and subsequently stirred for about 15 min at50-60° C. The reaction mixture was then refluxed at 75-80° C. to obtainclear solution. The reaction mixture was allowed to cool gradually andstirred for 2 hours and filtered. The wet-cake was washed with 20 mL ofmethyl ethyl ketone and dried under vacuum at 40° C. to 45° C. for 12hours. The X-ray powder diffraction discloses Form-III. (FIG. 3).

Example 5 Packing of Crystalline Forms—Form II & Form III of IvabradineHydrochloride (I)

The crystalline polymorph Form II & Form III of ivabradine hydrochlorideobtained as per example-3 and 4 was stored under nitrogen atmosphere andpacked in a non-permeable bag tied with a thread, keeping primarypacking inside a black color polyethylene bag containing oxygen bustersand sealing it, placing above the non-permeable bag inside a triplelaminated bag containing oxygen busters and sealing it, and placing thesealed triple laminated bag inside a closed high density polyethylene(HDPE) container.

While the present invention has been described in terms of its specificembodiments, certain modifications and equivalents will be apparent tothose skilled in the art and are intended to be included within thescope of the present invention.

1-35. (canceled)
 36. A storage stable crystalline Form II of ivabradinehydrochloride having characteristic X-ray powder diffraction peaks atabout 15.50°, 18.02°, 19.00°, 19.80°, 22.42°, 24.16°, and 25.46°±0.2°(2θ); comprising a packaging which includes placing crystallineivabradine hydrochloride under nitrogen atmosphere in a non-permeablebag or placing crystalline ivabradine hydrochloride in polyethylene bag,optionally containing oxygen busters and sealing it or placingcrystalline ivabradine hydrochloride in a triple laminated bag,optionally containing oxygen busters and sealing it or placingcrystalline ivabradine hydrochloride in triple laminated bag inside ahigh density polyethylene (HDPE) container.
 37. A storage stablecrystalline Form II of ivabradine hydrochloride having characteristicX-ray powder diffraction peaks at about 15.50°, 18.02°, 19.00°, 19.80°,22.42°, 24.16°, and 25.46°±0.2° (2θ) and has no detectable quantity ofcrystalline β, δ, γ, or amorphous forms after storage for 6 months at40° C. and a relative humidity of 75% or at 25° C. and a relativehumidity of 60%.
 38. A storage stable crystalline Form II of ivabradinehydrochloride which is characterized by X-ray powder diffraction peaksat about 8.05°, 8.69°, 12.11°, 15.50°, 16.18°, 18.02°, 19.00°, 19.80°,21.72°, 22.42°, 24.16°, 25.46° and 27.36°±0.2° (2θ).
 39. A crystallineForm II of ivabradine hydrochloride having characteristic X-ray powderdiffraction peaks at about 15.50°, 18.02°, 19.00°, 19.80°, 22.42°,24.16°, and 25.46°±0.2° (2θ) comprising a process of packaging whichincludes: (a) placing crystalline ivabradine hydrochloride undernitrogen atmosphere in a non-permeable bag and tying with a thread; (b)placing the bag of step (a) inside a black color polyethylene bag,optionally containing oxygen busters and sealing it; (c) placing the bagof step (b) inside a triple laminated bag, optionally containing oxygenbusters and sealing it; and (d) placing the sealed triple laminated baginside a high density polyethylene (HDPE) container and sealing it. 40.The storage stable crystalline Form II of ivabradine hydrochlorideaccording to claim 38, which is further characterized by a differentialscanning calorimetry (DSC) endothermic peak in the range of 197° C.-199°C.
 41. The storage stable crystalline Form II of ivabradinehydrochloride according to claim 38, which is prepared by the processcomprising: (a) providing a solution of ivabradine hydrochloride in oneor more solvents by heating at about 30° C. to about 120° C.; (b)obtaining the crystalline Form II of ivabradine hydrochloride by theremoval of the solvents; and (c) drying the crystalline Form II ofivabradine hydrochloride at about 40° C. to about 70° C., wherein thesolvent is at least one member selected from the group consisting ofmethanol, ethanol, isopropanol, butanol, dimethylformamide,dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, methyl ethylketone, acetone, methyl isobutyl ketone, ethyl acetate, butyl acetate,isopropyl acetate, acetonitrile, tetrahydrofuran,2-methyltetrahydrofuran, 1,4-dioxane, water and mixtures thereof. 42.The process according to claim 41, wherein the removal of the solventcomprises one or more of filtration, filtration under vacuum,decantation, centrifugation, distillation and distillation under vacuum.43. The storage stable crystalline Form II of ivabradine hydrochlorideaccording to claim 38, which is prepared by the process comprising: (a)contacting ivabradine base with hydrogen chloride in one or more firstsolvents to obtain ivabradine hydrochloride; (b) obtaining a solution ofivabradine hydrochloride in one or more second solvents; (c) optionallyadding water to the solution, heating the solution and cooling to obtainthe ivabradine hydrochloride wet-cake; and (d) treating the wet-cakewith one or more of first solvents to obtain the crystalline Form II ofivabradine hydrochloride.
 44. The process according to claim 43, whereinthe first is at least one member selected from the group consisting ofmethanol, ethanol, isopropanol, butanol, dimethylformamide, dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, methyl ethyl ketone,acetone, methyl isobutyl ketone, ethyl acetate, butyl acetate, isopropylacetate, acetonitrile, tetrahydrofuran, 2-methyl tetrahydrofuran,1,4-dioxane, water, or mixtures thereof.
 45. The process according toclaim 43, wherein the second solvent comprises one or more ofdimethylformamide, dimethylacetamide, dimethylsulfoxide,N-methylpyrrolidone, acetonitrile, tetrahydrofuran,2-methyltetrahydrofuran, 1,4-dioxane, water, or mixtures thereof.
 46. Apharmaceutical composition comprising a therapeutically effective amountof crystalline Form II of ivabradine hydrochloride according to claim 38together with one or more pharmaceutically acceptable carriers,excipients, or diluents.
 47. The storage stable crystalline Form II ofivabradine hydrochloride according to claim 38, having particle sizedistributions wherein the 10th volume percentile particle size (D10) isless than about 50 μm, the 50th volume percentile particle size (D50) isless than about 200 μm, or the 90th volume percentile particle size(D90) is less than about 400 μm, or any combination thereof.
 48. Thestorage stable crystalline Form II of ivabradine hydrochloride accordingto claim 38 is stable after exposure to a relative humidity of 75% at40° C. or 60% at 25° C. for a period of at least six months and issubstantially free from known crystalline forms or an amorphous form.